                Field of the Invention        
The present application relates to multivesicular liposome (MVL) formulations of methotrexate (MTX) which minimize the side effects of MTX while maintaining or improving efficacy.
Background Information
MTX is the primary first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA) and has demonstrated efficacy in other autoimmune diseases. MTX has also been used to treat certain cancers and cancer conditions. Cancer is a leading cause of death in the United States. Despite significant efforts to find new approaches for treating cancer, the primary treatment options remain surgery, chemotherapy and radiation therapy, either alone or in combination.
Over 500,000 patients are treated with immediate release MTX formulations worldwide (Sweierkot and Szechinski, Pharmacol Reports, 58, 473-492 (2006)). Because MTX causes significant plasma concentration-related side effects after each dose (nausea, vomiting, abdominal discomfort, taste disturbance, anorexia, dyspepsia, and diarrhea), it is usually taken once per week, on Saturday, so that the patient recovers by the work week. Side effects are primarily induced by high Cmax, which is a pharmacokinetic term meaning the maximum plasma concentration of the drug. At common efficacious doses, up to 80% of patients suffer these side effects and up to 35% of patients ultimately discontinue use of MTX even though it offers excellent efficacy in most patients (see R. J. McKendry et al., J Rheumatol 20:1850 (1993)). While many of the side effects of MTX appear to be gastrointestinal, some of them (for example nausea and vomiting) may be central nervous system (CNS) side effects so subcutaneous rather then oral administration does not necessarily ameliorate side effects.
Recent recommendations for the use of MTX in RA suggest that oral administration of MTX should be started at 10-15 mg/wk with escalation up to 20-30 mg/wk. High dose oral administration (>15 mg) is known to result in lower bioavailability than subcutaneous administration. This is due to the active absorption of MTX in the small intestine, a process which is capable of being saturated at higher doses (Stamp et al., Biomed Pharmacother 60 678-687 (2006)). Thus, parenteral administration can be used in cases of inadequate clinical response or intolerance for oral administration.
For RA, the efficacy of MTX is not related to the maximum plasma concentration (Cmax) of MTX but is directly related with its plasma area under the curve (“AUC”) (Hiraga et al., Mod Rheumatol 14:135 (2004)). MTX AUC correlates well with intracellular levels of MTX-polyglutamate, the latter of which are thought to provide the anti-inflammatory effect (Hornung et al., J. Rheumatol, 35, 1709-1715 (2008)). The standard AUC for oral immediate release dosage forms of MTX is 2466 mcg/L-hr. (Hoekstra et al., J Rheumatol, 31 645-48 (2004). The standard AUC for subcutaneous immediate release dosage forms of MTX is 3786 mgc/L-hr. Id.
Because orally administered MTX is absorbed rapidly (tmax 1-3 hour) and cleared rapidly (t1/2 8-10 hours), Cmax is difficult to control with conventional dosage forms. The tmax is the time after administration of a drug when the maximum plasma concentration is reached; that is when the rate of absorption equals the rate of elimination. The Cmax following oral and subcutaneous administration of traditional immediate release dosage forms of MTX are similar (Hoekstra et al., J Rheumatol, 31 645-648 (2004)).
Importantly, it has been observed that keeping the Cmax of MTX low reduces the incidence of the side effects of MTX administration to extremely low levels. It has been found that if Cmax is kept at 0.16 μmol/l or lower, the incidence of side effects significantly decreased. (Shoda et al., Mod. Rheumatol, 17: 311-316, 2007). A slow-release preparation which provides MTX in a low Cmax in addition to a therapeutically effective AUC (plasma concentration) over a prolonged period of time would provide significant benefits.
The embodiments of the present application provide such significant benefits. The instant MTX MVL formulations provide slow-release formulations which have a low Cmax of MTX and a therapeutically effective AUC that reduces the incidence of side effects to extremely low levels.
The instant MTX MVL formulations also provide the AUC necessary to maintain the efficacy of MTX. Thus, the slow-release MTX MVL formulations described in the present application achieve the AUC necessary for MTX to function as a first-line DMARD, while providing a Cmax low enough to reduce the incidence of the side effects of MTX use to extremely low levels.
In particular, the MVL used herein to deliver the MTX are defined as liposomes containing multiple non-concentric chambers within each liposome particle, resembling a “foam-like” matrix. Such particles are to be distinguished from multilamellar vesicles (MLV), also known as multilamellar liposomes, which enclose concentric aqueous compartments. A further distinct particle is the unilamellar vesicle (ULV), also known as a unilamellar liposome, which encloses a single internal aqueous compartment.